For a number of years, enveloped virus infections, including human immunodeficiency virus (HIV) infections, have posed serious global health concerns. Indeed, millions of new HIV infections are reported every year worldwide, with a majority of those new infections occurring mainly in developing regions where the availability of antiretroviral drug therapies is extremely limited, and, consequently, where Acquired Immunodeficiency Syndrome (AIDS) is among the leading causes of death [1]. The majority of infections are established via heterosexual transmission and condom use is currently the only available means to directly block this route of infection. As such, there is an urgent need for a woman-controlled, safe, effective, and inexpensive topical microbicide, at least until prophylaxis through vaccination becomes globally available [2, 3].
Current candidate microbicides include chemical and physical agents as well as biologicals, such as virion-inactivating agents, entry/fusion inhibitors, reverse transcriptase inhibitors, and a number of others. At this point in time, however, it is not known which type of anti-HIV agents will prove to be the most effective topical microbicides and, indeed, the blocking of HIV-1 mucosal transmission may require combinations of multiple agents [4, 5]. Therefore, to broaden the options for different combinations in HIV-1 microbicide development, it has been recognized that it is important to expand the candidate portfolio in each category of possible microbicide components.
In this regard, it has recently been further recognized that envelope (Env) glycans may constitute an attractive target for entry/fusion inhibitor-based microbicide development as Env glycans play critical roles in broad aspects of the viral life cycle ranging from Env folding in host cells to viral transmission and immune escape [7]. Indeed, it has been observed that the envelope (Env) gp120 is heavily glycosylated with N-linked glycans (NLGs), and generally accounts for more than half of the protein's molecular mass [6], with high-mannose-type glycans (HMGs) representing the major class.
Along these lines, lectins have attracted considerable attention in the search for Env glycan-targeting microbicide candidates as various naturally-occurring lectins have been shown to possess anti-HIV activities. Examples include algae-derived cyanovirin-N(CV-N) and griffithsin (GRFT), as well as plant-derived concanavalin A (Con A) and snowdrop lectin, among others [7]. More recently, a Jacalin-related lectin isolated from the banana fruit was shown to potently inhibit HIV-1 entry into target cells [8]. Although conceptually not a lectin, the human monoclonal antibody (mAb) 2G12 has also been shown to specifically bind to gp120 HMGs and thereby neutralize a wide spectrum of HIV-1 strains; thus, it has also been counted among the very few broadly neutralizing mAbs isolated to date [9,10].
One particular lectin that has recently been noted as having anti-HIV activity is actinohivin (AH). AH was first isolated from the actinomycete strain Longispora albida K97-0003T based on the inhibitory activity that was displayed in a syncytium formation assay [11]. Recent crystallographic analysis has revealed that AH is a monomeric protein and possesses three carbohydrate-binding (i.e., sugar-binding) domains [12]. Unlike several other known monosaccharide-specific anti-HIV lectins such as GRFT, Con A, and Galanthus nivalis agglutinin [7], however, AH specifically recognizes a cluster of multiple HMGs via a collaborative action among the protein's three sugar-binding sites [12, 13]. Because clustering HMGs is a unique feature of Env glycans and is not usually found on host human proteins [14], AH has been hypothesized to be a better anti-HIV-1 lectin with greater specificity to the virus. To date, however, and despite the detailed studies of AH's carbohydrate-binding specificity [12, 13, 15], limited investigation has been undertaken with respect to the protein's potential anti-HIV activity and with respect to how the protein may be manipulated to produce commercially relevant amounts and/or to provide increased anti-HIV activity.